Mitochondrion is the main organelle where free fatty acid is oxidized. After transported to mitochondrial matrix, fatty acid undergoes beta oxidation, generating acetyl- CoA as well as NADH and FADH2. Acetyl- CoA is further metabolized in mitochondrial matrix through TCA cycle and more NADH and FADH2 are generated. The high energy electrons carried by NADH and FADH2 are fed into electron transport chain (ETC) residing on the mitochondrial inner membrane. As the electrons travel through the ETC protein complexes, protons are pumped out across the membrane, establishing a proton gradient and membrane potential. ATP is synthesized when protons flow back to mitochondrial matrix through the FoF1-ATP synthase.
ETC activity is coupled to the energy requirement of the cells. When the energetic requirement is met, ETC and oxidation of acetyl-CoA are shut down. Mitochondrial uncoupling is a process which leads to proton influx across the mitochondrial inner membrane without passing through ATP synthase (illustrated in the red-dotted box of the schematic). This process de-couples mitochondrial oxidation from ATP synthesis, leading to a futile cycle of oxidation of acetyl-CoA. In essence, mitochondrial uncoupling can effectively promote fatty acid oxidation and eliminate intracellular fat accumulation.
Mitochondrial uncoupling occurs naturally in mammals, induced by mitochondrial uncoupler proteins (UCPs), such as UCP1. Mitochondrial uncoupling can also be induced by chemical uncouplers, which are usually lipophilic weak acids functioning within the mitochondrial inner membrane. They exist between the de-protonated form (U–) and protonated form (UH). Near the outer side of the membrane where proton concentration is high, uncouplers are protonated. The protonated uncouplers move to the matrix side, where they are deprotonated and release the protons to the mitochondrial matrix. As a result, as each acetyl-CoA is oxidized, few ATP are produced and most energy is dissipated as heat.
Mito BioPharma has developed a proprietary technology and a series of patent protected chemical uncouplers that are primarily distributed in liver. As the safety of induction of mitochondrial uncoupling in liver is well documented, Mito BioPharma lead compounds can potentially target a number of important diseases at their root causes in liver, including type 2 diabetes (reducing hepatic fat accumulation and hepatic insulin resistance) and NASH (reducing hepatic fat accumulation, sensitizing hepatic insulin resistance, reducing liver damage, preventing and reversing inflammation and fibrosis). Similarly, we have shown impact on hypercholesterolemia (reducing acetyl-CoA supply for cholesterol synthesis in liver), as well as liver cancer and hepatic metastases from other types of cancers (reducing lipid synthesis in cancer cells, which is required for providing membrane of proliferating cancer cells).